Abstract
Understanding the molecular basis of adipogenesis is vital to identify new therapeutic targets to improve anti-obesity drugs. The adipogenic process could be a new target in the management of this disease. Our aim was to evaluate the effect of GMG-43AC, a selective peroxisome proliferator-activated receptor γ (PPARγ) modulator, during adipose differentiation of murine pre-adipocytes and human Adipose Derived Stem Cells (hADSCs). We differentiated 3T3-L1 cells and primary hADSCs in the presence of various doses of GMG-43AC and evaluated the differentiation efficiency measuring lipid accumulation, the expression of specific differentiation markers and the quantification of accumulated triglycerides. The treatment with GMG-43AC is not toxic as shown by cell viability assessments after the treatments. Our findings demonstrate the inhibition of lipid accumulation and the significant decrease in the expression of adipocyte-specific genes, such as PPARγ, FABP-4, and leptin. This effect was long lasting, as the removal of GMG-43AC from culture medium did not allow the restoration of adipogenic process. The above actions were confirmed in hADSCs exposed to adipogenic stimuli. Together, these results indicate that GMG-43AC efficiently inhibits adipocytes differentiation in murine and human cells, suggesting its possible function in the reversal of adipogenesis and modulation of lipolysis.
Highlights
Adipogenesis is a complex process which includes the integration of many different signalling pathways and transcription factors [1]
Our findings demonstrate the inhibition of lipid accumulation and the significant decrease in the expression of adipocyte-specific genes, such as peroxisome proliferator-activated receptor γ (PPARγ), FABP-4, and leptin
These factors are rapidly expressed upon hormonal induction and could transcriptionally activate the C/EBPα and peroxisome proliferator-activated receptor γ (PPAR γ), which are the actors during the terminal phase of differentiation [13]
Summary
Adipogenesis is a complex process which includes the integration of many different signalling pathways and transcription factors [1]. Adipogenesis begins with a common multipotent precursor cell, that progressively goes through four sequential phases: pre-confluent proliferation, growth arrest, mitotic clonal expansion, and terminal differentiation [6,7,8,9,10]. The differentiation of preadipocytes into adipocytes is accompanied by alterations in gene expression and protein synthesis [11,12]. Mitotic clonal expansion is accompanied by the induction of CCAAT/enhancer-binding protein (C/EBP) β and δ. These factors are rapidly expressed upon hormonal induction and could transcriptionally activate the C/EBPα and peroxisome proliferator-activated receptor γ (PPAR γ), which are the actors during the terminal phase of differentiation [13]. All of them are necessary for the expression of adipocyte-specific genes, such as fatty acid binding protein (FABP-4), leptin, lipoprotein lipase, and others [11]
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